PROJECT SUMMARY/ABSTRACT Diabetic retinopathy (DR) represents the leading cause of blindness in working-age adults, with vision loss due to sequelae of proliferative retinal neovascularization and diabetic macular edema (DME). As such, it has traditionally been considered a disease of the retinal microvasculature. However, diabetes is also associated with retinal neuronal damage and diabetic patients exhibit visual functional deficits prior to the onset of clinically-apparent retinopathy. Increasing evidence from both diabetic patients and mouse models has further demonstrated progressive inner retinal neuronal loss which is present early in the course of the disease, preceding clinically-identified retinal vascular changes. The molecular mechanisms of early diabetic retinal neurodegeneration are unknown, although mitochondrial dysfunction has been implicated in DR, primarily in studies of whole retina and vascular endothelial cells. Mitochondrial dysfunction has also been shown to play a critical role in the pathogenesis of neurodegeneration in Parkinson?s disease (PD), with rare hereditary forms of PD associated with mutations in the mitophagy genes PINK1 and parkin. The laboratory of Dr. Ted Dawson, the principal investigator?s primary mentor, has identified a novel parkin-interacting substrate, PARIS, which regulates mitochondrial biogenesis via repression of PGC1a and has demonstrated that loss of dopaminergic neurons in the setting of parkin deficiency is driven primarily by impairments in mitochondrial biogenesis via the parkin/PARIS/PGC1a pathway. The role of mitochondrial biogenesis and its balance with mitophagy in retinal ganglion cells (RGCs) under diabetic conditions has not been explored. The hypotheses of this project are that (1) diabetes directly induces RGC dysfunction and loss via perturbations in the parkin/PARIS/PGC1a pathway of mitochondrial mass regulation, and that (2) dysfunctional RGCs in this setting secrete factors that directly affect the retinal vasculature. Under the additional mentorship of Dr. Don Zack and Dr. Gerard Lutty, and within the rich collaborative environment of the Johns Hopkins University School of Medicine, these hypotheses will be tested using in vitro approaches with primary cultured murine RGCs and hESC-derived RGCs, and in an in vivo mouse model of diabetes (streptozocin). The principal investigator is an MD/PhD clinician-scientist, who completed her training as a Vitreoretinal Surgeon, and now regularly cares for patients with vision loss due to diabetic retinal disease despite currently-available treatments, motivating her to investigate novel molecular pathways of disease pathogenesis. She is currently in year one of support from the Johns Hopkins Department of Ophthalmology K12 grant. Building upon the foundation of her PhD research, this K08 award will facilitate the additional expertise and training she needs to address her hypotheses and eventually transition to a position as an independent investigator in retinal neuronal metabolism, retinal neuroprotection, and neurovascular crosstalk.